Karen CRASTA
                       
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  Karen CRASTA  
  Lab Location: #4-02

email:
kccrasta@imcb.a-star.edu.sg
tel: 67783889
 
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  Key Publications  
 


Crasta K., Ganem N.J., Dagher R., Lantermann A.B., Ivanova E.V., Pan Y., Nezi L., Protopopov A., Chowdhury D., and Pellman D. (2012)
DNA breaks and chromosome pulverization from errors in mitosis.
Nature 482, 53-58.

Crasta K., Lim H.H., Giddings T.H. Jr, Winey M., and Surana U. (2008)
Inactivation of Cdh1 by synergistic action of Cdk1 and polo kinase is necessary for proper assembly of the mitotic spindle.
Nat Cell Biol 10, 665-675.

Crasta K., Huang P., Morgan G., Winey M., and Surana U. (2006)
Cdk1 regulates centrosome separation by restraining proteolysis of microtubule-associated proteins.
EMBO J 25, 2551-2563.

Krishnan V., Nirantar S., Crasta K., Cheng A.Y., and Surana U. (2004) 
DNA replication checkpoint prevents precocious chromosome segregation by regulating spindle behaviour.
Mol Cell 16, 687-700.

 

 
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    Karen CRASTA
 


Karen Crasta received her B.Sc. (Honours) in Microbiology from the National University of Singapore. She then obtained her Ph.D. at the Institute of Molecular and Cell Biology (IMCB) in the laboratory of Prof Uttam Surana in 2008 where she studied the molecular circuits governing mitotic spindle assembly using budding yeast as a model system. Following this, Karen received postdoctoral training at the laboratory of Prof David Pellman at the Dana-Farber Cancer Institute, Harvard Medical School, USA where she elucidated the mechanistic link between mitotic chromosome mis-segregation and tumourigenesis. She then returned to A*STAR IMCB as a Senior Research Fellow in 2012 before starting her own group in 2013.  Karen is currently a National Research Foundation Fellow at the Lee Kong Chian School of Medicine, NTU and was appointed Associate Professor in June 2013. She has been a Joint PI at A*STAR IMCB since September 2013. Karen is a recipient of a Research Associate Fellowship from Howard Hughes Medical Institute/HHMI (2008), A*STAR International Fellowship (2009), Elite Nanyang Assistant Professorship (2013) and the National Research Foundation Fellowship (2013).

 
    Genomic Instability and Cancer
     


Exploiting mitosis for cancer therapy

Intratumour heterogeneity (genetic, epigenetic, phenotypic) is evident in human cancers and presents a formidable challenge for cancer therapy as tumour cells vary in their sensitivity to chemotherapeutics due to genotypic or phenotypic variation. Consequently, addressing the biological basis for how cells acquire intratumoural heterogeneity has important implications for diagnostic and therapeutic approaches in the clinic.                         

Genomic instability has been proposed as an enabling characteristic for tumour formation. A type of genomic instability that frequently occurs in cancer cells is chromosomal instability (CIN) which is defined as the elevated rate of gain or loss of chromosomes, causing aneuploidy. CIN may generate cellular heterogeneity and potentially underlies the basis of clonal diversity, disease progression and resistance to cancer therapy.  Structures called micronuclei that arise from chromosome missegregation and occur commonly in preneoplastic lesions and cancers, are reflective of CIN. Micronuclear chromosomes can acquire breaks and potentially lead to chromosomal rearrangements, thus possessing tumourigenic potential (Crasta et al, 2012). Thus, one of our research aims is to characterize the functional role of micronuclear chromosomal abberations in CIN and clonal diversity of cancer disease. Additionally, it has been proposed that low rates of chromosome missegregation during mitosis can promote tumourigenesis, whereas missegregation of high numbers of chromosomes leads to cell death and tumor suppression. We wish to extend this in the chemotherapeutic context, and determine whether one could exploit micronuclear acquisition of massive DNA damage by elevating micronuclei frequencies to induce cell death since cells with unrepaired DNA damage tend to be eliminated via programmed cell death or apoptosis.  Since micronuclei are present in preneoplastic lesions and cancers, we will conduct studies to better define cell biological properties of micronuclei for utililty as a candidate biomarker for risk prediction as well as carry out profiling to correlate type and frequencies of micronuclei with molecular grades of cancers for patient stratification.  We are also working with a geriatrician to understand the genetic roots of the increased incidences of cancer and other metabolic diseases in older individuals since the single biggest risk factor for developing cancer today is aging.

 

   
 
 

To address these questions, we will be utilizing cell biology, biochemistry, high-resolution microscopy, chromosomal analyses, histochemistry, immunoFISH, spectral karyotyping, structural biology, functional genomics and bioinformatics.

Micronuclei formation is also one of the various outcomes following a prolonged mitotic arrest upon treatment with anti-mitotic drugs such as paclitaxel and vinblastine. Despite utilization of anti-mitotic drugs as front-line therapy for many cancers, very little is known about the mechanism behind how the prolonged mitotic arrest induced upon treatment culminates in cell death, as well as how and why some cancer cells escape the arrest and survive or die. Current research in our lab aims to have a deeper molecular understanding of drug response of cancer cells treated with these anti-mitotic drugs.  To gain insight into these issues, we will be taking a multidisciplinary approach and will utilize parallel integrative experimental (cell biology, biochemistry, high-resolution microscopy, genome-wide RNAi screening, loss-of-function genetic screening in a human cell line with a largely haploid karyotype pioneered by Thijn Brummelkamp et al, small-molecule screening) and biocomputational approaches to understand the intracellular dynamics governing cell fate decisions.  Our research hopes to identify novel cellular targets that could be of relevance to the development of combination therapies to improve sensitization of tumour cells, as well as provide insights into chemoresistance, a major setback in oncology.

Projects will be conducted in collaboration with groups at A*STAR (IMCB, GIS, IHPC, IMB), NTU, CSI, TTSH, NCC, Harvard Medical School and Imperial College London.